Heretofore, the most common process to separate narcotic alkaloids, which includes morphine, codeine, oripavine, thebaine, papaverine and narcotine (noscapine), is by solvent extraction. Separation includes both purification as well as color removal. The separated narcotic alkaloids are then purified by carbon adsorption and precipitation. Unfortunately, the carbon irreversibly adsorbs alkaloids of interest in addition to removing color and other unwanted substances. This creates a significant yield loss. Moreover, a yield loss will also occur in the supernatant in the alkaloid isolations. A solvent, such as ethanol, is typically required to promote purity in the precipitate. However, these solvent additions often cause yield loss in the supernatant that are not fully recovered. In some instances, multiple precipitations are required in order to achieve the desired purity. This greatly increases the complexity of the process since the supernatant streams must be recycled for recovery. These additional precipitations also require using a greater volume of raw narcotic alkaloids in the process with longer cycle times. Furthermore, the precipitation process can be lengthy in addition to the time that is sometimes required for heating and cooling. Also, some precipitations require extended filtration time due to the particle size of the narcotic alkaloid that is eventually produced.
Other drawbacks to the current process of purifying narcotic alkaloids with solvent extraction, adsorption and precipitation include a multiple of manual solid handling operations to recover the narcotic alkaloid. These operations lead to greater operator exposure to narcotics with the associated reliance on engineering controls and personal protective equipment. This operation can be monotonous as well as tedious.
Although there have been modifications to the precipitation process to improve both the solvent extraction and alkaloid precipitations, there are still limitations since the separation process requires significantly different solubility. Improving the purity after precipitation often reduces yield in the supernatant.
One specific example of this type of modified solvent extraction is found in U.S. Pat. No. 6,054,584 issued to Ma, et al. on Apr. 25, 2000, which discloses a process for extracting only morphine from opium where the opium is dissolved in a basic alcoholic solution. The basic alcoholic solution is then filtered and the alcohol is removed from the filtrate to leave a residue. The residue is then extracted with a basic aqueous solution having a pH of at least 11. The basic aqueous solution may be filtered to remove any solid matter remaining after the aqueous extraction step, and then is stirred with a sufficient amount of salt to avoid the formation of an emulsion. The basic aqueous solution or filtrate is then extracted with benzene or toluene. Next, the pH of the basic aqueous filtrate is adjusted to a pH of between 8.5 to 9.5, which allows the morphine to precipitate for recovery.
There are a number of different ways to achieve adsorption besides the use of carbon. One way to achieve adsorption is through ion exchange. Although this was done with both codeine and morphine, it has the limitation of requiring a low feed concentration. This is due to the need of using high pH flushes, which can cause precipitation. Any precipitation can potentially compromise the entire purification process. Another disadvantage to this approach is that significant salt is required so that another step of either dialysis or reverse osmosis is required for ion-removal.
Yet another way to achieve adsorption is through polar interaction or normal phase adsorption. Although this method is successful, it requires the extensive use of organic solvents. Moreover, although the alkaloids can be separated from each other, more evaporation is required.
Still another way to achieve adsorption is through separating alkaloids from other components based on molecular size by utilizing a membrane. This purification method is limited to either removing larger or smaller components. There is a yield loss due to the inherent imperfections in the membrane.
Any use of analytical chromatography on narcotic alkaloids would teach an individual of ordinary skill in the art away from using preparative chromatography. Unlike preparative chromatography, analytical chromatography generally requires complete separation of each peak, as measured by ultraviolet absorbance. This is achieved by loading an infinitely small mass of the feed onto the column, and using a small particle size diameter (often less than 5 micrometers (196.85 microinches)) in the stationary phase. The small particle size generates much higher pressures than those found in preparative chromatography. These higher pressures mandate the use of very large, strong and expensive chromatography equipment, which would negate the commercial viability for this analytical process. The equipment would also be very large in consideration that an infinitely small mass of feed is loaded in each run. In preparative chromatography, the objective is to recover the desired feed component with the required purity. The desired component can be recovered with impurities, so long as the impurities are within specification limits. The particle size of the stationary phase is small enough to achieve the separation, but is often greater than 10 micrometers (393.70 microinches). This limits the pressure drop generated. Also, in preparative chromatography, the maximum amount of feed is loaded with the constraint of attaining the desired product quality. This allows the product to leave the column with a maximum concentration, which then minimizes the size of the downstream equipment, especially any evaporating or concentrating units.
Any use of analytical chromatography on narcotic alkaloids would teach an individual of ordinary skill in the art away from using preparative chromatography. Unlike preparative chromatography, analytical chromatography generally requires peak separation, as measured by ultraviolet absorbance, since it makes it extremely difficult to determine when the different narcotic alkaloids are eluting from the chromatography column. Moreover, in direct contrast to preparative chromatography, analytical chromatography generally prohibits the elution of impurities with each product having a separate peak. Likewise, the loading ratio utilized with analytical chromatography equipment along with the small particle size of the expensive stationary phase media generates much higher pressures than those found in preparative chromatography. These higher pressures mandate the use of very large, strong and expensive chromatography equipment, which would negate the commercial viability for this analytical process. The present invention is directed to overcoming one or more of the problems set forth above. These deficiencies and shortcomings include, but are not limited to, narcotic alkaloid yield loss, tedious manual solid handling operations such as the loading and unloading of centrifuges or filters, reliance on protective equipment by the operator, extensive processing steps and potential multiple precipitations in order to achieve the requisite purity requirements.